Overview of Genetic Testing

As the science of genomics advances, genetic testing is becoming more commonplace in the clinic. Yet most genetic tests are not regulated, meaning that they go to market without any independent analysis to verify the claims of the seller. The Food and Drug Administration (FDA) has the authority to regulate genetic tests, but it has to date only regulated the relatively small number of genetic tests sold to laboratories as kits. Whereas the Centers for Medicare and Medicaid Services (CMS) does regulate clinical laboratories, it does not examine whether the tests performed are clinically meaningful. Since the 1990s, expert panels and members of Congress have expressed concern about this regulatory gap and the need for FDA to address it. In response, the FDA in 2010 announced plans to expand its regulation to all genetic tests; this expansion has yet to take place. In the interim, FDA continues to regulate test kits, and has begun to regulate genomics tools in clinical research.

Introduction to Genetic Testing

The term "genetic testing" covers an array of techniques including analysis of human DNA, RNA, or protein. Genetic tests are used as a health care tool to detect gene variants associated with a specific disease or condition, as well as for non-clinical uses such as paternity testing and forensics. In the clinical setting, genetic tests can be performed to determine the genetic cause of a disease, confirm a suspected diagnosis, predict future illness, detect when an individual might pass a genetic mutation to his or her children, and predict response to therapy. They are also performed to screen newborns, fetuses, or embryos used in in vitro fertilization for genetic defects.

The first genetic tests were for the detection of chromosomal abnormalities (see karyotype) and mutations in single genes causing rare, inherited disorders like cystic fibrosis. In recent years, however, the variety of tests has greatly expanded. There are now tests involving complex analyses of a number of genes to, for example, identify one's risk for chronic diseases such as heart disease and cancer, or to quantify a patient's risk of cancer reoccurrence. There are also many tests to predict the effectiveness of therapeutics and guide their administration. Furthermore, NHGRI is pursuing research to enable the clinical use of multi-gene panels, whole exome sequencing (analysis of all a patient's genes), and whole genome sequencing (analysis of a patient's entire genetic code), to detect, for instance, the cause of an undiagnosed disease or a cancerous tumor.

Federal Regulation of Genetic Tests

Three federal agencies play a role in the regulation of genetic tests: CMS, FDA, and the Federal Trade Commission (FTC).

CMS is responsible for regulating all clinical laboratories performing genetic testing, ensuring their compliance with the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The objective of CLIA is to certify the clinical testing quality, including verification of the procedures used and the qualifications of the technicians processing the tests. It also comprises proficiency testing for some tests. More details of CLIA are available in this factsheet

How to evaluate a genetic test:

Is the test accurate and reliable? (Analytical validity)

Is the test result medically meaningful? (Clinical validity)

Does the test improve healthcare? (Clinical utility)

The FDA has the broadest authority in terms of regulating the safety and effectiveness of genetic tests as medical devices under the Federal Food, Drug, and Cosmetic Act. Whether FDA regulates a test is determined by how it comes to market. A test may be marketed as a commercial test "kit," a group of reagents used in the processing of genetic samples that are packaged together and sold to multiple labs. More commonly, a test comes to market as a laboratory-developed test (LDT), where the test is developed and performed by a single laboratory, and where specimen samples are sent to that laboratory to be tested. The FDA regulates only tests sold as kits and, to date, has practiced "enforcement discretion" for LDTs.

The degree of FDA oversight of a genetic test is based on its intended use and the risks posed by an inaccurate test result. The FDA categorizes medical devices, including genetic tests, into three separate classes, ranging from class I, for relatively low risk products, to class III, where tests are subject to the greatest level of scrutiny. A complete list of approved human genetic tests is listed here.

FDA oversight also includes pharmacogenomics, which is the use of genomic information to help predict how an individual might respond to a particular drug, to identify individuals who might experience an adverse reaction to taking a drug, or to assist in selecting the optimal dosage of a drug. Part of the FDA's oversight of marketed drugs is to ensure that manufacturers provide information on drug labels about genetic markers that is relevant for drug safety and effectiveness. A list of approved pharmacogenomic drugs is available here.

Compared to FDA and CMS, the FTC's regulatory authority is relatively narrow, and is limited to how tests are advertised. The Commission has the authority to regulate advertising that delivers health-related information to consumers to ensure that it is not false or misleading.

FDA Regulation and Genomics Research

Congress granted FDA authority to oversee the use of medical devices in clinical research in the same 1976 Medical Device Amendments as authorized their premarket review of commercially marketed devices. Unlike the enforcement discretion practiced in the realm of commercial genetic tests, the agency has never discriminated between LDTs and kits in exercising this authority on the use of genetic devices within clinical research.

With genome, exome, and targeted panels from advanced sequencing platforms now being tested in clinical settings, some studies involving these technologies will require an Investigational Device Exemptions (IDE) from the FDA before enrolling participants. The IDE-similar to the Investigational New Drug application (IND) - is designed to ensure that there is appropriate oversight of the research use of new medical devices that have not been cleared or approved by FDA. It requires investigators to provide FDA with information on the device being used in the study, including the analytic validity for the researchers' intended use (i.e., whether the test measures what the researchers believe it measures).

In order to help researchers consider how their research may fit within the requirements for an IDE, NHGRI held an IDE and Genomics Workshop on June 10th, 2016 to discuss how and when IDE regulations might apply to genomics research. Please visit the IDE and Genomics Workshop webpage for new resources that resulted from this workshop, including video footage. Information resulting from the workshop should not be viewed as official guidance from NHGRI, NIH or FDA, and researchers and their Institutional Review Boards should ensure they have read the official FDA resources on the subject before participants are enrolled.

FDA Plans to Regulate LDTs

In 2010, FDA announced that it plans to regulate LDTs, citing the ways in which the market has changed, such as the growing distance between commercial laboratories doing the testing and the physician ordering the test and the increased complexity of some genetic tests.

The FDA announcement came after repeated calls over many years from advisory panels for the FDA to regulate LDTs. As long ago as 1997, a joint NIH-Department of Energy Task Force on Genetic Testing recommended the formation of a committee to advise the HHS Secretary on this and associated issues. (Final Report). The resulting Secretary's Advisory Committee on Genetic Testing called in 2000 for the FDA to review tests for their diagnostic or prognostic value before allowing them to go to market and followed up a year later with further recommendations on how to best classify tests for assessment. The committee's successor, the Secretary's Advisory Committee on Genetics, Health and Society, issued another report in 2008 again recommending that the FDA regulate all laboratory tests, regardless of whether they are sold as kits or marketed as LDTs.

These recommendations were not implemented, but the topic was highlighted again when a 2006 investigation by the Government Accountability Office (GAO) of direct-to-consumer genetic tests (report) called many of the scrutinized tests as "medically unproven and meaningless" and misleading for consumers. Senator Edward Kennedy (D-MA) partnered with Senator Gordon Smith (R-OR) to co-author the Laboratory Test Improvement Act in 2006 to expand FDA oversight to all clinical laboratory tests. Then-Senator Barack Obama (D-IL), with co-sponsorship from Senator Richard Burr (R-NC), also introduced the Genomics and Personalized Medicine Act, with provisions to strengthen the regulation of genetic tests. Despite the bipartisan sponsorship of the two bills, both lacked the necessary support to progress through Congress. The GAO re-visited the issue in 2010 with a report on the deceptive practices of direct-to-consumer tests, calling the results of such tests as "misleading and of little or no practical use."

On July 31, 2014, the FDA gave Congress notice that it would be announcing draft guidelines on the regulation of laboratory developed tests (LDTs) in the next 60 days.

US Government Accountability Office
Nutrigenetic testing: tests purchased from four websites mislead consumers [testimony before the Special Committee on Aging, US Senate]. Washington, DC: US Government Accountability Office; Jul 27. 2006

US Government Accountability Office
Direct-to-consumer genetic tests: misleading test results are further complicated by deceptive marketing and other questionable practices. Washington, DC: US Government Accountability Office; Jul 22. 2010